A New Treatment Paradigm for Human Leukocyte Antigen (HLA)-Associated Diseases The proposed project will build the foundation of a new interdisciplinary team consisting of 2 independent laboratories: a UM Medical School group headed by Joseph Holoshitz, MD, whose longstanding focus has been on the pathobiology of rheumatoid arthritis (RA), and a group at the UM College of Pharmacy, headed by Henry Mosberg, PhD, an expert in medicinal chemistry. The 2 teams will join efforts to rationally design new therapeutic compounds for RA, based on a highly innovative concept, discussed briefly below. Under the parent NIAMS-funded R01 grant, we have recently uncovered a novel mechanism of HLA- disease association, by showing that the single most important genetic risk factor for RA, a HLA-DRB1- coded sequence motif called 'shared epitope' (SE), is a signal transduction ligand that activates Th17 polarization and increases disease severity in experimental arthritis. Moreover, based on these data, we have rationally designed a prototypic small inhibitory molecule that exerts potent anti-arthritis therapeutic effects at pM-range doses. The long-term goal of the new collaboration is to establish the foundations on which multidisciplinary teams of investigators will be able to design new therapeutic agents for HLA-associated diseases. The requested BIRT funds will be used to test-pilot the idea, focusing on RA. Based on the success of the proposed studies in RA, the program could be extended in the format of P01, or multi-PI R01s, to other HLA- associated conditions. Specifically, in the studies proposed here, we will: 1. Design compound analogs with improved bioavailability and decipher their conformation (Mosberg); 2. Determine their membrane permeability and oral availability (Holoshitz); 3. Determine the biologic effects of the new compounds both in vitro and in an experimental model of RA (Holoshitz). The project conforms well with the BIRT idea: It involves a newly formed interdisciplinary team from distinct scientific fields and schools; the underlying concept is highly novel; the project involves a high-risk/high yield research pursuit; it will examine a paradigm-changing theory, and; the proposed studies will build the foundations on which novel drugs could be developed in a wide-range of HLA-associated conditions.